Expanding the genotype–phenotype correlations in Alport syndrome: novel mutations, digenic inheritance, and genetic modifiers

Abstract

Abstract Background Alport syndrome (AS) is the second most prevalent genetic cause of kidney failure, behind autosomal-dominant polycystic kidney disease, affecting at least one in 5000 individuals worldwide. AS is caused by COL4A3, COL4A4, and COL4A5 mutations. It is characterized as three distinct disorders of type IV collagen 3/4/5 based on a genetic evaluation: X-linked, autosomal, and digenic. About two-thirds of AS cases are X-linked (XLAS), 15% are autosomal recessive (ARAS), and 20% are autosomal dominant (ADAS). The spectrum of phenotypes associated with AS ranges from increasing renal disease with extrarenal abnormalities to isolated hematuria. Coinherited genetic mutations contribute significantly to clinical severity and variability. Methods In this study, an AS panel (COL4A3/COL4A4/COL4A5) and clinical exome sequencing (CES) were performed on 18 patients. Results Nineteen specific AS mutations, including 15 novel mutations, were found in these 18 cases, which included 17 Turkish families and 1 Syrian family. Digenic inheritance was observed in one patient, and eight coinherited genetic mutations were discovered. Conclusions This research reveals many novel AS mutations and shows robust genotype–phenotype heterogeneity in the disease. The results expand the clinical and molecular scope of AS and clarify the ADAS and digenic AS phenotypes, further enhancing our understanding of the complex nature of AS and its association with genetic modifiers. The data broaden the spectrum of AS-related gene mutations and provide new insights on genotype–phenotype correlations in AS.